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High-affinity CD16A polymorphism associated with reduced risk ofsevere COVID-19.
No full textCD16A is an activating Fc receptor on NK cells that mediates antibody-dependent cellular cytotoxicity (ADCC), a key mechanism in antiviral immunity. However, the role of NK cell-mediated ADCC in SARS-CoV-2 infection remains unclear, particularly whether it limits viral spread and disease severity or contributes to the immunopathogenesis of COVID-19. We hypothesized that the high-affinity CD16AV176 polymorphism influences these outcomes. Using an in vitro reporter system, we demonstrated that CD16AV176 is a more potent and sensitive activator than the common CD16AF176 allele. To assess its clinical relevance, we analyzed 1,027 patients hospitalized with COVID-19 from the Immunophenotyping Assessment in a COVID-19 cohort (IMPACC), a comprehensive longitudinal dataset with extensive transcriptomic, proteomic, and clinical data. The high-affinity CD16AV176 allele was associated with a significantly reduced risk of ICU admission, mechanical ventilation, and severe disease trajectories. Lower anti-SARS-CoV-2 IgG titers were correlated to CD16AV176; however, there was no difference in viral load across CD16A genotypes. Proteomic analysis revealed that participants homozygous for CD16AV176 had lower levels of inflammatory mediators. These findings suggest that CD16AV176 enhances early NK cell-mediated immune responses, limiting severe respiratory complications in COVID-19. This study identifies a protective genetic factor against severe COVID-19, informing future host-directed therapeutic strategies
Facts and Hopes: Toward the Next Quantum Leap in Melanoma.
No full textOutcomes from advanced melanoma, the deadliest of the skin cancers arising from melanocytes and capable of widely metastasizing, have greatly improved, with death rates decreasing for patients with American Joint Committee on Cancer stage 4 melanoma by 3% to 5% annually over the past 10 years. This improvement is a result of advances in both targeted therapy and immunotherapy. BRAF and MEK inhibitors for advanced melanoma have led the way for targeted cancer strategies and first-in-class approvals for immune checkpoint blockers targeting CTLA4, PD-1, and LAG3; T-cell engager therapy targeting the antigen gp100; and tumor-infiltrating lymphocyte therapy. All of these have contributed to enhanced outcomes, including long-term durable responses in up to half of patients with advanced disease. In addition, adjuvant and neoadjuvant approaches are reducing the risk of relapse in patients with stage II and III disease. Because of its immunogenicity and defined targetable mutations, melanoma drug development has led the way for novel approaches in cancer research. Yet additional approaches are needed for patients with recurrent or nonresponsive disease or rare subtypes, including mucosal, acral, and uveal melanomas. Progress in modified T cells, including T-cell receptor, chimeric antigen receptor T-cell (CAR-T), and CRISPR gene editing strategies, holds promise for future therapeutics. Continued understanding of the molecular and immune tumor microenvironment and heterogeneity, as well as understanding the microbiome and numerous diverse approaches to topics ranging from prevention to mechanisms of treatment resistance and novel therapeutic approaches, will optimize opportunities to further decrease melanoma mortality
Stand-alone small low-profile braided stents for challenging unruptured posterior inferior cerebellar artery aneurysms compared to conventional endovascular methods: A cohort study.
No full textObjectivePosterior inferior cerebellar artery (PICA) aneurysms are uncommon and may be challenging to treat, especially if they are very small saccular or dissecting pseudoaneurysms at proximal and mid-PICA locations. They are usually technically difficult to treat with conventional reconstructive endovascular methods. We present our experience with PICA aneurysms treated by a stand-alone small, low-profile stent with a moderate flow-diverting effect (low-profile visualized intraluminal support junior (LVIS Jr)) compared to conventional endovascular methods.MethodsSingle institution cases of treated unruptured PICA aneurysms from 2015 to May 2022 were retrospectively reviewed. Patient characteristics, pre-and postoperative images, and last clinical and radiological outcomes were analyzed. Comparative statistical analysis was used.ResultsNine cases of unruptured PICA aneurysms treated with stand-alone LVIS Jr (group 1) and seven cases treated with other conventional methods (group 2) were identified. The mean age was 56 versus 61.43 years, sex was female in 7 versus 6 cases, and the left side was involved in 7 versus 4 cases in group 1 and group 2, respectively. All aneurysms were in the proximal PICA segment except for one case in the mid-PICA segment aneurysm in each group. There was a difference in aneurysm type in both groups (p = 0.008). All aneurysms were of saccular type except for five dissecting types in group 1 and 2 in group 2. The mean aneurysm size was 1.91 ± 0.62 in group 1 and 9.04 ± 5.82 mm in group 2 (p \u3c 0.0002). In group 2, treatment was with PICA sacrifice (one case), primary aneurysm coiling (three cases), stent-assisted coiling (one case), and flow diverter (two cases). Complications were only puncture site-related that occurred once in each group. There were no differences in mean clinical or radiological follow-up. Aneurysm recurrence with retreatment occurred in two cases in each group. All patients had an mRS 0-2 at the last follow-up.ConclusionIn selected cases, unruptured small or dissecting PICA aneurysms may be treated safely and effectively using single stand-alone LVIS Jr. Prospective studies are needed to validate safety and efficacy
Risk prediction for ALS using semi-competing risk models with applications to the ALS Natural History Consortium dataset.
No full textNew Insights into Upper Tract Urothelial Carcinoma: Lessons Learned from the ROBUUST Collaborative Study.
No full textUpper tract urothelial carcinoma (UTUC) is a rare malignancy, representing only 5-10% of urothelial carcinoma. The mainstay of treatment for high-risk patients is radical nephroureterectomy. Given the aggressive behavior of this disease, additional treatments could be required perioperatively in terms of chemotherapy (CHT), either in a neoadjuvant or adjuvant setting. On the other hand, low-risk and selected cases can be managed with kidney-sparing surgery (KSS). The ROBotic surgery for Upper tract Urothelial cancer STudy (ROBUUST) is an ongoing international, multicenter registry of patients undergoing surgery for UTUC. After conducting a literature search in February 2025 using the MEDLINE (via PubMed) and Embase databases, we identified 14 studies based on the ROBUUST data analyses. There are several key topics concerning UTUC that remain under debate and were therefore addressed in these studies, focusing on preoperative evaluation and planning, surgical techniques and intraoperative procedures, additional perioperative treatments, and outcomes. The ROBUUST registry has served as a valuable source for a growing body of investigations focusing on various aspects of UTUC treatment planning, decision-making, and outcomes, providing innovative tools and enabling large-scale, novel analyses
Identification and targeting of regulators of SARS-CoV-2-host interactions in the airway epithelium.
No full textThe impact of SARS-CoV-2 in the lung has been extensively studied, yet the molecular regulators of host-cell programs hijacked by the virus in distinct human airway epithelial cell populations remain poorly understood. Some of the reasons include overreliance on transcriptomic profiling and use of nonprimary cell systems. Here we report a network-based analysis of single-cell transcriptomic profiles able to identify master regulator (MR) proteins controlling SARS-CoV-2-mediated reprogramming in pathophysiologically relevant human ciliated, secretory, and basal cells. This underscored chromatin remodeling, endosomal sorting, ubiquitin pathways, as well as proviral factors identified by CRISPR assays as components of the viral-host response in these cells. Large-scale drug perturbation screens revealed 11 candidate drugs able to invert the entire MR signature activated by SARS-CoV-2. Leveraging MR analysis and perturbational profiles of human primary cells represents an innovative approach to investigate pathogen-host interactions in multiple airway conditions for drug prioritization
Education as Empowerment: Training Emergency Department Nurses to Provide Safe Care to Delivering Mothers and Their Newborns, in a Low-Resource Setting
No full textComprehensive Profiling of Acral Lentiginous Melanoma Reveals Downregulated Immune Activation Compared to Cutaneous Melanoma.
No full textAcral lentiginous melanoma (ALM) is a rare and insufficiently understood subtype of melanoma lacking in effective treatment options. Recent work has demonstrated that the response of ALM to immune checkpoint blockade is inferior to that of cutaneous melanoma (CM). Here we performed bulk genomic and transcriptomic sequencing of tumor tissue from 28 ALM and 5692 CM cases. Similar to prior studies, ALM was associated with a significantly lower incidence of point mutations, including in the TERT promoter and BRAF, but increased numbers of gene amplifications, notably of CCND1, HMGA2, and MDM2. Reactome pathway analysis revealed enhancement of keratinization and PI3K/AKT signaling pathways. Overall immunogenicity was decreased in ALM, which possessed lower IFNγ (p \u3c 0.001) and T-cell inflammatory (p = 0.03) pathway scores than CM. Despite higher computationally inferred levels of myeloid dendritic cells (p = 0.006), neoantigen load independent of predicted HLA binding affinity was lower (p \u3c 0.01) in ALM versus CM. Assessment of classical and nonclassical HLA mRNA levels revealed upregulation of HLA-G, suggesting alternative ALM immune evasion pathways in the setting of lower PD-L1 expression (p = 0.005). Additional research is needed to better understand and therapeutically target signaling networks in the ALM tumor microenvironment
